論文 - 詳細
| RRC ID | 44834 |
|---|---|
| 著者 | Nanjo S, Yamada T, Nishihara H, Takeuchi S, Sano T, Nakagawa T, Ishikawa D, Zhao L, Ebi H, Yasumoto K, Matsumoto K, Yano S. |
| タイトル | Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. |
| ジャーナル | PLoS One |
| Abstract |
PURPOSE:Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. EXPERIMENTAL DESIGN:Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. RESULTS:The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. CONCLUSIONS:Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically. |
| 巻・号 | 8(12) |
| ページ | e84700 |
| 公開日 | 2013-1-1 |
| DOI | 10.1371/journal.pone.0084700 |
| PII | PONE-D-13-35113 |
| PMID | 24386407 |
| PMC | PMC3873434 |
| MeSH | Acrylamides / pharmacology* Afatinib Amino Acid Substitution Animals Cell Line, Tumor Crizotinib Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics ErbB Receptors / metabolism Female Humans Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology Lung Neoplasms / genetics Lung Neoplasms / pathology Mice Mice, SCID Mutation, Missense Phosphorylation Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins c-met / metabolism Pyrazoles / pharmacology* Pyridines / pharmacology* Pyrimidines / pharmacology* Quinazolines Xenograft Model Antitumor Assays |
| IF | 2.74 |
| 引用数 | 32 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5 |